Engineering Enzymes for New‐to‐Nature Carbene Chemistry

Athavale, Soumitra V.; Chen, Kai; Arnold, Frances H.

doi:10.1002/9783527829170.ch4

Cited by 4 publications

(3 citation statements)

References 120 publications

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“…Myoglobin, a related heme-containing protein, has been used to generate trifluoromethyl-substituted cyclopropanes via the highly reactive trifluoromethylcarbene, representing the first step away from carbonyl-stabilised carbenes. [99] As discussed in several reviews, [100][101][102][103] the iron-carbenoids formed in the active sites of heme-containing enzymes (cytochrome P450, cytochrome c, myoglobin) undergo the same depth and breadth of transformations as with traditional carbene reactivity in organic synthesis. [104][105][106][107][108][109][110][111][112] An important feature of these reactions is that there is no observable dimerization of the diazo reagent.…”

Section: Cytochrome P450s (Ec 114à à ) Cytochrome Cs (Ec 19à à ) and ...mentioning

confidence: 99%

Reagent Engineering for Group Transfer Biocatalysis

Reed,

Seebeck

2023

Angew Chem Int Ed

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Biocatalysis has become a major driver in the innovation of preparative chemistry. Enzyme discovery, engineering and computational design have matured to reliable strategies in the development of biocatalytic processes. By comparison, substrate engineering has received much less attention. In this minireview, we highlight the idea that the design of synthetic reagents may be an equally fruitful and complementary approach to develop novel enzyme‐catalyzed group‐transfer chemistry. This review discusses key examples from the literature that illustrate how synthetic substrates can be devised to improve the efficiency, scalability and sustainability, as well as the scope of such reactions. We also provide an opinion as to how this concept might be further developed in the future aspiring to replicate the evolutionary success story of natural group transfer reagents such as adenosine triphosphate (ATP) or S‐adenosyl methionine (SAM).

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Section: Cytochrome P450s (Ec 114à à ) Cytochrome Cs (Ec 19à à ) and ...mentioning

confidence: 99%

Reagent Engineering for Group Transfer Biocatalysis

Reed,

Seebeck

2023

Angew Chem Int Ed

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“…Iron porphyrin-catalyzed carbene transfer reaction is one of the most powerful synthetic strategies in organic chemistry . With the extensive investigations on the excellent catalytic performance of cytochrome P450 enzymes for numerous biochemical reactions, iron porphyrin carbenes (IPCs) have been generally recognized as the reactive intermediates for a broad range of iron porphyrin-catalyzed carbene transfer reactions starting from diazo compounds, including cyclopropanation, C–H, , N–H, and O–H insertion, multicomponent reactions, and olefination of carbonyl compounds as well as many other types of transformations (Scheme a) . As a result, studies toward the structure and reactivity of IPCs have always been one of the central tasks in iron porphyrin chemistry. ,, …”

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confidence: 99%

Synthesis and Characterization of Donor–Acceptor Iron Porphyrin Carbenes and Their Reactivities in N–H Insertion and Related Three-Component Reaction

Wang

Sheng

et al. 2023

J. Am. Chem. Soc.

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Iron porphyrin carbenes (IPCs) have been extensively recognized as the reactive intermediates in various iron porphyrin-catalyzed carbene transfer reactions. While donor–acceptor diazo compounds have been frequently used for such transformations, the structures and reactivities of donor–acceptor IPCs are less explored. To date, no crystal structures of donor–acceptor IPC complexes have been reported, and therefore, the involvement of IPC intermediacy for such transformations lacks direct evidence. Here we report the synthesis and NMR characterization of several donor–acceptor IPC complexes from iron porphyrin and corresponding donor–acceptor diazo compounds. The X-ray crystal structure of an IPC complex derived from a morpholine-substituted diazo amide was obtained. The carbene transfer reactivities of those IPCs were tested by the N–H insertion reactions with aniline or morpholine as well as the three-component reaction with aniline and γ,δ-unsaturated α-keto ester based on electrophilic trapping of an ammonium ylide intermediate. Based on these results, IPCs were identified as the real intermediates for iron porphyrin-catalyzed carbene transfer reactions from donor–acceptor diazo compounds.

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“…For the asymmetric construction of the crucial benzylic C−C or C-heteroatom bond, a plethora of methods has been described. Approaches that use chiral auxiliaries, metal catalysts, organocatalysts, and enzymes, among others, are known (2)(3)(4)(5). However, despite its potential as a general approach to benzylic stereocenters, the catalytic enantioselective reaction of a nucleophile with a benzylic cation remains underdeveloped.…”

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confidence: 99%

Taming secondary benzylic cations in catalytic asymmetric S _N 1 reactions

Singh,

Zhu,

et al. 2023

Science

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Benzylic stereogenic centers are ubiquitous in natural products and pharmaceuticals. A potentially general, though challenging, approach toward their selective creation would be asymmetric unimolecular nucleophilic substitution (S N 1) reactions that proceed through highly reactive benzylic cations. We now report a broadly applicable solution to this problem by identifying chiral counteranions that pair with secondary benzylic cations to engage in catalytic asymmetric C−C, C−O, and C−N bond-forming reactions with excellent enantioselectivity. The critical cationic intermediate can be accessed from different precursors via Lewis- or Brønsted acid catalysis. Key to our strategy is the use of only weakly basic, confined counteranions that are posited to prolong the lifetime of the carbocation, thereby avoiding nonproductive deprotonation pathways to the corresponding styrene.

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Engineering Enzymes for New‐to‐Nature Carbene Chemistry

Cited by 4 publications

References 120 publications

Reagent Engineering for Group Transfer Biocatalysis

Reagent Engineering for Group Transfer Biocatalysis

Synthesis and Characterization of Donor–Acceptor Iron Porphyrin Carbenes and Their Reactivities in N–H Insertion and Related Three-Component Reaction

Taming secondary benzylic cations in catalytic asymmetric S _N 1 reactions

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Engineering Enzymes for New‐to‐Nature Carbene Chemistry

Cited by 4 publications

References 120 publications

Reagent Engineering for Group Transfer Biocatalysis

Reagent Engineering for Group Transfer Biocatalysis

Synthesis and Characterization of Donor–Acceptor Iron Porphyrin Carbenes and Their Reactivities in N–H Insertion and Related Three-Component Reaction

Taming secondary benzylic cations in catalytic asymmetric S N 1 reactions

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Taming secondary benzylic cations in catalytic asymmetric S _N 1 reactions